Comparison of Coronary Artery Bypass Grafting With Drug-Eluting Stent Implantation for the Treatment of Multivessel Coronary Artery Disease

Comparison of Coronary Artery Bypass Grafting With Drug-Eluting Stent Implantation for the Treatment of Multivessel Coronary Artery Disease Jeong Hoon Yang, MD, Hyeon-Cheol Gwon, MD, Soo Jin Cho, MD, Joo Yong Hahn, MD, Jin-Ho Choi, MD, Seung Hyuk Choi, MD, Young Tak Lee, MD, Sang Hoon Lee, MD, Kyung Pyo Hong, MD, and Jeong Euy Park, MD Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea CARDIOVASCULAR Background. The introduction of drug-eluting stents (DESs) has demonstrated superiority over the bare metal stent in reducing the incidence of restenosis. We investigated the clinical outcomes of DESs versus coronary artery bypass grafting (CABG) in a series of patients with multivessel disease. Methods. Patients with multivessel disease who underwent percutaneous coronary intervention with DESs (n 441) or CABG (n 390) between March 2003 and March 2005 were included. The primary outcomes of this study were defined as the absence of major adverse cardiac and cerebral events at 12 months, including death from any cause, cerebrovascular accidents, acute myocardial infarctions, and repeat revascularization after percutaneous coronary intervention with DESs or CABG. Results. During 12 months of follow-up, the mortality rate was also not significantly different between the two groups (2.1% versus 3.2%, p 0.170). The incidences of composite death, cerebrovascular accident, and acute myocardial infarction were not significantly different between groups (2.8% versus 3.9%, p 0.180). The rate of overall major adverse cardiac and cerebral events was higher in DES group compared with the CABG group (13.0% versus 4.2%, p < 0.001), as driven by the higher incidence of myocardial infarction and revascularization. Conclusions. The incidences of death and cerebrovascular event were not significantly different between the DES and CABG groups in the patients with multivessel disease. However, the overall incidence of major adverse cardiovascular and cerebral events seems to be favorable for CABG group even this era of DESs. (Ann Thorac Surg 2008;85:65 70) 2008 by The Society of Thoracic Surgeons Percutaneous coronary intervention (PCI) for the treatment of multivessel coronary artery disease has been limited by restenosis, which developed in 30% to 40% of patients treated with balloon angioplasty and in 20% to 25% of patients treated with a bare metal stent (BMS) [1]. The introduction of the drug-eluting stent (DES) has dramatically reduced the restenosis rate, so the indications for PCI in patients with multivessel disease have been broadened [2]. A recent large-scale study For editorial comment, see page 25 showed that the 1-year clinical outcome of patients treated with DESs was almost equivalent to that of coronary artery bypass grafting (CABG) in patients with multivessel disease [3]. However, this study compared the current DES technique with a historical CABG group recruited from a previous study. The results of CABG have also improved thanks to better perioperative management and the better surgical experience [4, 5]. Accepted for publication June 7, 2007. Address correspondence to Dr Gwon, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea; e-mail: hcgwon@smc.samsung.co.kr. We investigated the clinical outcomes of the current DES versus CABG approaches in a series of patients with multivessel CAD. Material and Methods This was a single-center retrospective registry study comparing DESs and CABG among patients with multivessel disease. This study received Institutional Review Board approval, and informed consent was waived. In the DES group, patients were treated with a sirolimuseluting stent (Cypher, Johnson & Johnson, Miami Lakes, FL) or a paclitaxel-eluting stent (TAXUS, Boston Scientific, Natick, MA). Patient Selection The patients were recruited from the cardiovascular catheterization and coronary artery bypass surgery databases of Samsung Medical Center, Seoul, Korea. Patients were included if they underwent PCI with a DES or CABG between March 2003 and March 2005 for 2 or more significant de novo lesions located in different major epicardial coronary arteries. Exclusion criteria included patients with previous coronary intervention or CABG, cardiogenic shock, acute myocardial infarction (AMI) 2008 by The Society of Thoracic Surgeons 0003-4975/08/$34.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2007.06.027

CARDIOVASCULAR 66 YANG ET AL Ann Thorac Surg DES VS CABG IN MULTIVESSEL CAD 2008;85:65 70 requiring emergency PCI, congenital heart disease, concomitant valve surgery, mechanical complications (eg, ventricular septal defect), free wall rupture, and significant left main trunk disease. Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting As a treatment option, a DES or CABG was selected by the preference of patients and doctors. CABG was preferred in patients with more extensive disease, two or more chronic total occlusions, severe left ventricular dysfunction, and diabetes mellitus. In the DES group, we tried functional revascularization rather than complete anatomic revascularization by dilating the culprit lesions that had a stenosis diameter of more than 75% in relatively big arteries. In CABG group, arterial grafting with off-pump coronary artery bypass was preferred technique, when possible. Carotid Doppler imaging was checked routinely and brain magnetic resonance imaging, if necessary. We did not limit the use of aspirin or heparin before and after surgery. Study End Points and Follow-Up Baseline clinical, laboratory, and angiographic characteristics were collected from the databases and medical records. Follow-up clinical status was documented by review of hospital records, telephone interviews, or by contacting general practitioners. Coronary angiography was not routinely monitored. The primary outcomes of this study were to determine Table 1. Baseline Characteristics of the Patients Variable a DES (n 441) CABG (n 390) p Value Age, years 63 10 63 8 0.382 Women 127 (28.8) 117 (30.0) 0.704 Stable angina 261 (59.2) 190 (48.7) 0.003 Q-wave myocardial 80 (18.1) 60 (15.4) 0.289 infarction Diabetes mellitus 163 (37.0) 189 (48.5) 0.001 Hypertension 282 (63.9) 238 (61.0) 0.385 Smoking 133 (30.2) 125 (32.1) 0.556 Prior cerebrovascular 54 (12.2) 42 (10.8) 0.287 accident Disease of LAD 381 (86.4) 384 (98.5) 0.001 CAD 2-vessel 256 (58.0) 90 (23.1) 0.001 CAD, 3-vessel 185 (42.0) 300 (76.9) 0.001 Ejection fraction b 0.58 0.12 0.53 0.14 0.001 Total cholesterol (mg/dl) 176 43 176 41 0.809 Creatinine (mg/dl) 1.09 0.78 1.17 1.06 0.213 Parsonnet score 8.4 7.0 9.2 5.8 0.064 Patients with Parsonnet score 15 68 (15.4) 65 (16.7) 0.625 a Continuous data are presented with the standard deviation; categoric data are presented as number (%). b Echocardiographic examination was performed in 328 patients in the DES group, and 390 patients in the CABG group. CABG coronary artery bypass grafting; CAD coronary artery disease; DES drug-eluting stent; LAD left anterior descending artery. Table 2. Procedural Characteristics of the Patients Characteristic N (%) or Mean SD DES patients 441 Angiographic success 425 (96.4) Angiographic stenosis/patient 3.9 1.65 Stents/patient 1.5 0.78 Artery with significant stenosis RCA 345 (78.2) LAD 381 (86.4) LCX 342 (77.6) Vessel dissection or perforation 9 (2.0) CABG patients 390 Bypassed vessels RCA 346 (88.7) LAD 384 (98.5) LCX 353 (90.5) Type of grafts Vein 100 (25.6) LIMA 386 (99.0) RIMA 363 (93.1) GEA 39 (10.0) Radial artery 6 (1.5) Graft composition Arterial grafts only 290 (74.4) Venous grafts only 2 (0.5) Vein arterial 98 (25.1) Off-pump surgery 309 (79.2) Distal anastomoses 3.8 1.04 Reoperation for bleeding 5 (1.3) Wound complication 20 (5.1) CABG coronary artery bypass grafting; DES drug-eluting stent; GEA gastroepiploic artery; LAD left anterior descending artery; LCX left circumflex artery; LIMA left internal mammary artery; RCA right coronary artery; RIMA right internal mammary artery. the incidences of any 12-month major adverse cardiac and cerebral event (MACCE), defined as a composite event of death from any cause, AMI, cerebrovascular accidents (CVA), or repeat revascularization after PCI or CABG. The secondary outcomes of the study were the Table 3. Revascularization Characteristics in the Drug- Eluting Stent Group Characteristic DES Group, n (%) Patients 441 Anatomic complete revascularization a 111 (25.2) Ballooning stents 40 (9.1) Stents only 71 (16.1) Functional complete revascularization b 275 (62.4) Ballooning stents 67 (15.2) Stents only 208 (47.2) a An anatomically complete revascularization was accomplished when all vessels with 50% diameter stenosis were treated. b A functionally complete revascularization was accomplished when all vessels with 75% diameter stenosis were treated. DES drug-eluting stent.

Ann Thorac Surg YANG ET AL 2008;85:65 70 DES VS CABG IN MULTIVESSEL CAD Table 4. Cumulative Clinical Event Rate During Follow-Up Event DES, n (%) CABG, n (%) p Value Patients 441 390 Death (all-cause) 0 30 days 1 (0.2) 3 (0.8) 0.140 0 12 months 9 (2.1) 12 (3.2) 0.170 Cardiac death 0 30 days 1 (0.2) 2 (0.5) 0.257 0 12 months 6 (1.4) 6 (1.6) 0.408 CVA 0 30 days 0 2 (0.5) 0.079 0 12 months 3 (0.7) 3 (0.8) 0.448 AMI 0 30 days 2 (0.5) 0 0.076 0 12 months 6 (1.4) 1 (0.3) 0.034 Repeat PCI 0 30 days 1 (0.2) 0 0.159 0 12 months 39 (9.2) 2 (0.5) 0.001 CABG 0 30 day 0 1 (0.3) 0.159 0 12 month 6 (1.4) 1 (0.3) 0.034 Death/AMI/CVA 0 30 day 2 (0.5) 4 (1.0) 0.173 0 12 month 12 (2.8) 15 (3.9) 0.180 MACCE 0 30 day 2 (0.5) 4 (1.0) 0.173 0 12 months 56 (13.0) 16 (4.2) 0.001 AMI acute myocardial infarction; CABG coronary artery bypass grafting; CVA cerebrovascular accident; DES drug-eluting stent; MACCE major adverse cardiac and cerebral event; MI myocardial infarction; PCI percutaneous coronary intervention. incidences of 30-day MACCE, 30-day and 12-month composite deaths, CVA and AMI. Definitions A significant lesion was defined as stenosis of at least 50% of the diameter of a vessel with a reference diameter of more than 1.5 mm by visual estimation. The procedural success of PCI was defined as thrombosis in myocardial infarction (TIMI) flow grade 3, with a final residual stenosis of less than 30% without death, MI, or emergency CABG before hospital discharge. A complete anatomic revascularization was considered as accomplished when all vessels with 50% or more diameter stenosis were successfully revascularized. A complete functional revascularization was considered as accomplished when all vessels with a 75% or more diameter stenosis were successfully revascularized. Death was defined as any postprocedural death and was considered of cardiac origin unless there was documentation of another cause. MI was defined as the presence of significant new Q waves in at least two electrocardiographic leads and chest discomfort associated with cardiac enzyme elevation more than three times the upper limit of the normal value. CVA was defined as ischemic neurologic deficits lasting more than 24 hours. The Parsonnet score, which was originally developed to assess the risk for cardiac surgery, was used to estimate the baseline risk of the patients [6]. According to this scoring system, the patients were stratified as high risk if their score exceeded 15. Statistical Analysis All values are presented as the mean standard deviation. Comparisons between continuous data were tested using unpaired t tests or Wilcoxon ranked scores when applicable. Categoric data were tested using the Fisher exact test or the 2 test. Event-free survival was estimated by the Kaplan-Meier method and compared with the log-rank test. A stepwise multivariate Cox proportional hazards model was created with the use of baseline clinical characteristics and procedure-related variables to identify independent predictors of MACCE. Preselected variables were revascularization modality (CABG versus PCI), age, sex, Q-wave myocardial infarction, diabetes mellitus, disease of the left anterior descending artery (LAD), three-vessel disease versus two-vessel disease, 67 CARDIOVASCULAR Fig 1. Twelve months after the revascularization procedure, rates of death, and composite death, cerebrovascular accident, or myocardial infarction were not statistically different between the two revascularization strategies. However, the patients treated with a drug-eluting stent (DES, thin lines) were more likely to require repeat revascularization than those in treated with coronary artery bypass grafting (CABG, thick lines). (A) Actuarial survival in the DES versus CABG groups. (B) Kaplan-Meier estimates of survival free of composite death, cerebrovascular accident, or myocardial infarction. (C) Kaplan-Meier estimates of survival free of death, myocardial infarction, cerebrovascular accident, or repeated revascularization.

CARDIOVASCULAR 68 YANG ET AL Ann Thorac Surg DES VS CABG IN MULTIVESSEL CAD 2008;85:65 70 Table 5. Cumulative Clinical Event Rate at 12 Months According to Treatment Modality and the Presence of Treated Diabetes DM Group, n (%) Non-DM Group, n (%) Event DES CABG p Value DES CABG p Value Patients 163 189 278 201 Death 6 (3.8) 7 (3.8) 0.492 3 (1.1) 5 (2.6) 0.133 CVA 2 (1.3) 1 (0.5) 0.250 1 (0.4) 2 (1.0) 0.220 AMI 4 (2.5) 1 (0.5) 0.075 2 (0.8) 0 0.081 CABG 3 (2.0) 1 (0.5) 0.124 3 (1.1) 0 0.042 Repeat PCI 19 (12.4) 1 (0.5) 0.001 20 (7.4) 1 (0.5) 0.001 Composite death/cva/ami 9 (5.6) 9 (4.9) 0.382 3 (1.1) 6 (3.1) 0.081 MACCE 29 (18.3) 9 (4.9) 0.001 27 (9.9) 7 (3.6) 0.003 AMI acute myocardial infarction; CABG coronary artery bypass grafting; CVA cerebrovascular accident; DES drug-eluting stent; DM diabetes mellitus; LAD left anterior descending artery; MACCE major adverse cardiac and cerebral event; PCI percutaneous coronary intervention. renal impairment (serum creatinine 150 mmol/l) and Parsonnet score. All tests were two-tailed, and p 0.05 was considered significant. All analyses were performed with SPSS 10.0 software (SPSS Inc, Chicago, IL). Results From the databases, 1212 patients were identified as having had a revascularization for multivessel disease, and 831 patients who met the selection criteria were enrolled. The DES group had 441 patients and the CABG group had 390 patients. A 12-month clinical follow-up was completed in 420 patients (95.2%) in the DES group and 375 (96.2%) in the CABG group. Baseline and Procedural Characteristics Baseline clinical and procedural characteristics are summarized in Tables 1 and 2. The proportions of high-risk patients (Parsonnet score 15) were similar between the two groups: 15.4% in the DES group versus 16.7% in the CABG group (p 0.625). Revascularization characteristics are summarized in Table 3. In the DES group, complete anatomic revascularization was achieved in 111 patients (25.2%) and a complete functional revascularization was accomplished in 275 (62.4%). In the CABG group, 382 (97.9%) patients had complete anatomic revascularization. Clinical Outcomes at 30 Days and 12 Months The average follow-up duration was 21.1 6.7 months in the DES group and 23.1 8.8 months in the CABG group. Table 4 and Figure 1 show cumulative clinical outcomes of the study populations. The 12-month rates of MI and repeat PCI and CABG were significantly higher in the DES group than in the CABG group (p 0.034, 0.001, and 0.034, respectively). Six of 7 patients with MI were diagnosed in the hospital and 1 by a general practitioner. The cumulative rates of composite death, CVA, or MI were not significantly different between groups (p 0.180). The cumulative 12-month MACCE rate was significantly higher in the DES group at 13.0% than the 4.2% rate in the CABG group (p 0.001). Influence of Diabetes on Clinical Outcomes Clinical outcomes according to the presence of treated diabetes are summarized in Table 5. In the DES group, the rates of composite death/mi/cva and MACCE were significantly higher among patients with diabetes (p 0.011 and 0.012, respectively). In the CABG group, no significant differences were found in the rates of clinical events, including death, CVA, MI, CABG, repeat PCI, and overall MACCE between the diabetic and nondiabetic patients. Predictors of Major Adverse Cardiac and Cerebral Events Cox regression analysis was performed to recognize predictors of MACCEs at 12 months (Table 6). The significant univariate predictors were group (CABG versus PCI), disease of LAD, and the Parsonnet score. In the multivariate Cox regression model, the significant predictors of MACCEs were revascularization modality (CABG versus PCI) and Parsonnet score. Comment This study showed that there were no differences in the rates of composite death, CVA or AMI at 12 months between PCI with a DES and CABG for the patients with multivessel CAD. However, Kaplan-Meier curves reveal Table 6. Significant Predictors of Major Adverse Cardiac and Cerebral Events Variable p Value Hazard Ratio (95% CI) Univariate analysis PCI vs CABG 0.001 LAD disease 0.026 Parsonnet score 0.029 Multivariate analysis PCI vs CABG 0.001 4.0 (2.3 6.8) Parsonnet score 0.008 1.0 (1.0 1.1) CABG coronary artery bypass grafting; CI confidence interval; LAD left anterior descending artery; PCI percutaneous coronary intervention.

Ann Thorac Surg YANG ET AL 2008;85:65 70 DES VS CABG IN MULTIVESSEL CAD Table 7. Cumulative Major Adverse Cardiac and Cerebral Events in Relation to Type of Graft and Use of Cardiopulmonary Bypass in the Coronary Artery Bypass Grafting Group On-pump, n (%) OPCAB, n (%) p Value Complete Arterial Grafts, n (%) Noncomplete Arterial Grafts, n (%) 69 p Value CARDIOVASCULAR Patients 81 309 290 100 Composite death/cva/ami 0 30 day 3 (4.7) 1 (0.3) 0.060 2 (0.7) 2 (2.0) 0.192 0 12 month 6 (7.4) 9 (3.0) 0.080 11 (3.9) 4 (4.1) 0.475 MACCE 0 30 day 3 (4.7) 1 (0.3) 0.060 2 (0.7) 2 (2.0) 0.192 0 12 month 6 (7.4) 10 (3.4) 0.100 12 (4.3) 4 (4.1) 0.466 AMI acute myocardial infarction; CVA cerebrovascular accident; MACCE major adverse cardiac and cerebral event; OPCAB off-pump coronary artery bypass; PCI percutaneous coronary intervention. evidence of a crossover in the mortality and composite end point (Fig 1A, B), suggesting that the outcomes of CABG group will be better in the long-term. Moreover, the patients treated with a DES were more likely to require repeat revascularization, and the rate of MACCEs was still higher than that of the CABG group. This study designated DESs and CABG as elective treatment strategies for patients with multivessel CAD at a single center. Although our study was analyzed retrospectively, this study is one of only a few trials reporting the clinical outcomes of patients with multivessel CAD treated with a DES versus CABG. During the BMS era, there was a meta-analysis of the results of the Arterial Revascularization Therapies Study (ARTS) [7], Surgery or Stent Trial [8], Argentine randomized study (coronary angioplasty with stenting versus coronary bypass surgery in patients with multivessel disease) [9], and the Medical Angioplasty or Surgery II Study [10]. This analysis confirmed that there was no difference in 1-year mortality between BMSs and surgical revascularization among 3051 patients [11]. In the present study, the mortality rate in the CABG group was 3.2% at 12 months, similar to the 2.8% among patients from the meta-analysis [11] and not significantly different from the 2.1% in the DES group (p 0.170). The composite incidence of death, CVA, and MI was 2.8% in the DES group and 3.9% in the CABG group, significantly lower than in patients from the meta-analysis (8.7% in the BMS group versus 9.1% in the CABG group) [11]. The need for repeat revascularization caused by restenosis remains the major limitation, however. After the introduction of the DES approach, different registries have reported a reduction in restenosis for the treatment of multivessel CAD [12 16]. In the present study, compared with the BMS era, the rate of repeat revascularizations by PCI or CABG was improved to 10.6% in the DES group and to 0.8% in the CABG group. Repeat revascularization practices remained higher in the DES group compared with the CABG group, but the differences have narrowed in the present study relative to the meta-analysis in the BMS era (10.6% versus 0.8% and 19.2% versus 4.4%, respectively) [11]. The ARTS-II trial was a multicenter, nonrandomized, open-label stratified trial designed to evaluate sirolimuseluting stent implantation in patients with multivessel CAD using a surgical group taken from ART I as an historical control [13]. There was no difference in the incidence of major adverse cardiovascular events at 1 year between the ART-II DES trial registry patients and the CABG randomized patients in the ART-I trial (10.4% versus 11.6%) [2]. However, the CABG group may have been underestimated by nonconcurrent comparison in the ART-II trial. In our study, evaluated by concurrent comparison, the overall rate of MACCEs was 13.0% in the DES group and 4.2% in the CABG group. The improvements of technique and tools in both groups depend on major advances. However, we have also seen the implementation of more aggressive adjunctive pharmacology, such as the use of aspirin, clopidogrel, glycoprotein IIb/IIIa inhibitors, and statins; better control of risk factors, and improving surgical experience [5, 17]. We assumed that the rate of overall MACCEs would be markedly improved in the CABG group compared with the DES group because off-pump surgery or use of arterial-only grafts in our institution was more frequently performed than in previous studies [18 20]. Although complete arterial grafting was not significantly better than noncomplete arterial grafting, off-pump surgery showed a trend of better result than on-pump surgery, particularly in the short-term result (Table 7). In the present study, the rate of off-pump surgery was 79.2%, higher than the rate of 3% to 64% among patients from the meta-analysis [18], and the rate of complete arterial grafts was 74.4%, higher than 12% in run-in phase of the Synergy Between PCI with the TAXUS DES and Cardiac Surgery (SYNTAX) study [5]. The incidence of mortality at 12 months was not significantly different in both groups for patients with and without diabetes (p 0.492 versus p 0.133). In the Korean Multicenter Revascularization Registry study, the 1-year mortality rate among patients with diabetes in the PCI group was only 0.8-fold that of the CABG group; however, the 3-year mortality was 1.9-fold higher [21]. Beyond the first year, progression of underlying atherosclerosis may play a greater role in mortality for such patients [22]. The short duration of follow-up in the present study may therefore have masked any significant differences. Compared with the CABG group, however, the rates of composite death/mi/cva and overall MACCEs were significantly higher in the patients with

CARDIOVASCULAR 70 YANG ET AL Ann Thorac Surg DES VS CABG IN MULTIVESSEL CAD 2008;85:65 70 diabetes in the DES group. CABG may thus still be viewed as the optimal treatment for diabetic patients with multivessel CAD in the DES era. Our study has some limitations. First, it was not a randomized trial in that the selection of treatment was likely influenced by patient characteristics and by patient and doctor preferences. Especially, patients with more extensive disease, two or more chronic total occlusions, severe left ventricular dysfunction, and diabetes preferred CABG than a DES in treatment options. As summarized in Table 1, the study populations differed greatly. Although the Parsonnet score was similar between two groups and multivariate analysis was performed, we cannot control potentially important unknown variables. Second, it is not clear if the results of this study can be applied in general because of the high rate of complete arterial graft and off-pump surgery, whereas a relatively small number of stents were used in PCI group. Third, a follow-up loss of 4.3% may be high considering the lost patients could have had a higher incidence of events. Finally, the long-term implications of our findings are not evident because this study limited the follow-up duration to 12 months. Considering the Kaplan-Meier curve of survival and event-free survival was crossed at 2 years, CABG group will have better result in the longterm follow-up. In conclusion, it seems that the incidences of death and cerebrovascular events were not significantly different between the DES and CABG groups in the patients with multivessel disease. However, the overall incidence of major adverse cardiovascular and cerebrovascular events seems to be favorable for the CABG group even this era of DES. 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